Identification of a Brainstem Circuit Controlling Feeding

Abstract

Hunger, driven by negative energy balance, elicits the search for and consumption of food. While this response is in part mediated by neurons in the hypothalamus, the role of specific cell types in other brain regions is less well defined. Here, we show that neurons in the dorsal raphe nucleus, expressing vesicular transporters for GABA or glutamate (hereafter, DRN and DRN neurons), are reciprocally activated by changes in energy balance and that modulating their activity has opposite effects on feeding-DRN neurons increase, whereas DRN neurons suppress, food intake. Furthermore, modulation of these neurons in obese (ob/ob) mice suppresses food intake and body weight and normalizes locomotor activity. Finally, using molecular profiling, we identify druggable targets in these neurons and show that local infusion of agonists for specific receptors on these neurons has potent effects on feeding. These data establish the DRN as an important node controlling energy balance. PAPERCLIP.

Combined Social and Spatial Coding in a Descending Projection from the Prefrontal Cortex

“…To further compare PL-NAc, PL-Amyg, and PL-VTA neurons, we performed RNA-seq on each population using the projection-specific molecular profiling technology Retro-TRAP (Nectow et al 2015; Ekstrand et al 2014; Nectow, Moya, et al 2017) (Figures 1G and S1C). This revealed significant differences in enrichment levels in 2745 out of 15041 genes examined (Figure 1H and Table S1; p<.01, 1-way ANOVA adjusted for multiple comparisons).…”

“…The dissected brain tissue from 6 mice were combined to form a single sample (number of samples-Amyg: 3, NAc: 3, VTA: 2). As described previously (Nectow et al 2015; Ekstrand et al 2014; Nectow, Moya, et al 2017; Nectow, Schneeberger, et al 2017), GFPL10-positive ribosomes were then immunoprecipitated using a 2 hr GFP immunoprecipitation (GFP IP). qPCR analysis was performed using TaqMan assays for the targeted genes to determine differential enrichment (Figure S1C).…”

Hypothalamic Structural and Functional Imbalances in Anorexia Nervosa

“…In this context, our data raise the intriguing possibility that glutamatergic dysfunction plays a role in the pathophysiology of AN, or indeed, of other eating disorders. Targeting the glutamatergic drive, which normally suppresses feeding [33,34,37], could thus hold therapeutic potential for treating this disorder. Moreover, the similarities between human AN and the constitutive activation of hypothalamic glutamatergic neuronal populations in mice suggest that the latter could constitute a novel and appropriate animal model for further studies of this disease.…”

ΔFosB Requires Galanin, but not Leptin, to Increase Bone Mass via the Hypothalamus, but both are needed to increase Energy expenditure

“…Thus, further research is needed to resolve the leptin–serotonin link in the control of bone. Of interest, the brainstem Raphe nucleus, via which the leptin pathway was suggested to take its course, was recently shown to contain GABAergic and glutamatergic neurons, which exert reciprocal and bidirectional regulation of feeding and body weight, independently of leptin . Transcriptional analysis of these neurons revealed that glutamatergic but not GABAergic Raphe nucleus terminals also express markers of serotonin synthesis.…”

“…Of interest, the brainstem Raphe nucleus, via which the leptin pathway was suggested to take its course, was recently shown to contain GABAergic and glutamatergic neurons, which exert reciprocal and bidirectional regulation of feeding and body weight, independently of leptin. (64) Transcriptional analysis of these neurons revealed that glutamatergic but not GABAergic Raphe nucleus terminals also express markers of serotonin synthesis. These findings raise the possibility that these excitatory and inhibitory brainstem neurons may also be involved in the regulation of bone biology independently of leptin.…”